IDENTIFICATION OF ANTIRHEUMATOID ARTHRITIS LIGANDS USING IN SILICO ANALYSIS

Objective: The purpose of the research was to implement molecular docking simulation to investigate the anti-inflammatory capability of against thioesterase-2, an essential component of the inflammatory reaction in humans. Methods: After obtaining three-dimensional structures of arthritis ligand and thioesterase-2 protein from IUPHAR/BPS Guide to PHARMACOLOGY, PUBCHEM, and RCSB PDB databases server, ligands with suitable absorption, distribution, metabolism, and excretion (ADME) properties were docked against thioesterase-2 protein using PyRx 0.8 and AutoDock tools 1.5.7. Results: Indomethacin showed better binding affinity to thioesterase-2. Conclusion: In light of its promising binding affinities with thioesterase-2, indomethacin could be taken into consideration as a prospective pharmacological agent for thioesterase-2 inhibition, according to molecular docking simulation and SWISS ADME evaluation

In silico design of small molecules targeting cathepsin-k for the treatment of osteoarthritis

Purpose: To investigate cathespin-K as an alternative drug target for the development of a new therapy for osteoarthritis (OA) in humans.Method:  In silico molecular docking simulation-based virtual screening was used to identify probable lead molecules with significant binding affinities for the target receptor, and acceptable pharmacokinetic profiling. Lamarkian genetic algorithm was used for molecular docking simulation, while various physicochemical parameters such as molecular weight, calculated partition coefficient, topological polar surface area, and hydrogen bond acceptor and donor counts were evaluated for their pharmacokinetic profile.Results: The compound, ZINC05386901, was found to be a potent inhibitor of human cathespin-K protein with excellent pharmacokinetic properties, and had no toxic effects.Conclusion: The designed inhibitor molecule for cathespin-K protein is a promising lead molecule for further structure-based discovery of novel drugs for the treatment of OA.Keywords: Osteoarthritis, Cathepsin-K, Drug design, Ligan

Deciphering of interactions between platinated DNA and HMGB1 by hydrogen/deuterium exchange mass spectrometry

A high mobility group box 1 (HMGB1) protein has been reported to recognize both 1,2-intrastrand crosslinked DNA by cisplatin (1,2-cis-Pt-DNA) and monofunctional platinated DNA using trans-[PtCl2(NH3)(thiazole)] (1-trans-PtTz-DNA). However, the molecular basis of recognition between the trans-PtTz-DNA and HMGB1 remains unclear. In the present work, we described a hydrogen/deuterium exchange mass spectrometry (HDX-MS) method in combination with docking simulation to decipher the interactions of platinated DNA with domain A of HMGB1. The global deuterium uptake results indicated that 1-trans-PtTz-DNA bound to HMGB1a slightly tighter than the 1,2-cis-Pt-DNA. The local deuterium uptake at the peptide level revealed that the helices I and II, and loop 1 of HMGB1a were involved in the interactions with both platinated DNA adducts. However, docking simulation disclosed different H-bonding networks and distinct DNA-backbone orientations in the two Pt-DNA-HMGB1a complexes. Moreover, the Phe37 residue of HMGB1a was shown to play a key role in the recognition between HMGB1a and the platinated DNAs. In the cis-Pt-DNA-HMGB1a complex, the phenyl ring of Phe37 intercalates into a hydrophobic notch created by the two platinated guanines, while in the trans-PtTz-DNA-HMGB1a complex the phenyl ring appears to intercalate into a hydrophobic crevice formed by the platinated guanine and the opposite adenine in the complementary strand, forming a penta-layer π–π stacking associated with the adjacent thymine and the thiazole ligand. This work demonstrates that HDX-MS associated with docking simulation is a powerful tool to elucidate the interactions between platinated DNAs and proteins

Design of dual inhibitors of human TNF-α and IL-6 with potentials for the treatment of rheumatoid arthritis

Purpose: To design dual inhibitors of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) with potentials for the treatment of rheumatoid arthritis (RA). Methods: Tumor necrosis factor α (TNF-α) and IL-6 were investigated as potential drug targets for the treatment of RA. Dual inhibitors targeting both TNF-α and IL-6 were designed simultaneously using molecular docking simulation-based in silico virtual screening technique. National Cancer Institute (NCI) diversity set-II consisting of 1818 diverse ligands were screened against both drug targets in order to identify potential lead molecules on the basis of lowest binding energy. Results: Out of 1818 diverse ligand molecules present in the NCI diversity set-II, five lead molecules were selected based on best binding interactions with both target receptors. The results of toxicity profiling showed that compounds ZINC19701771 and ZINC06576501 lacked major toxicity-associated functional groups linked to mutagenic, tumorigenic, irritant and reproductive effects. However, ZINC03898665 and ZINC05015095 possessed some mutagenic and reproductive effects. Compound ZINC01757986 also showed a high chance of mutagenicity. Conclusion: These results indicate that the two lead molecules (ZINC19701771 and ZINC06576501) that showed reliable physicochemical properties can serve as potential candidates for development of anti-arthritis drug for effective inhibition of human TNF-α and IL-6 receptors

Immunosuppressive effect of voacamine from Voacanga africana Stapf based on SPRi experiment

Purpose: To investigate the affinity of a bis-indole alkaloid - voacamine from Voacanga Africana Stapf for IL-2Rα - and its immunosuppressive effect on concanavalin A-induced T cell proliferation and lipopolysaccharide -induced B cell proliferation in vitro. Methods: Surface plasmon resonance imaging (SPRi) was used to screen the target protein of voacamine, while CCK-8 kit was used to evaluate cytotoxicity. Mitogen-induced proliferation assay was carried out to assess the inhibitory effect of voacamine on Con A-induced T cell proliferation and LPSinduced B cell proliferation. The binding characteristics of voacamine were investigated using a binding model with IL-2Rα constructed based on molecular docking simulation. Results: Voacamine had a high-affinity for IL-2Rα with an equilibrium dissociation constant (KD) of 1.85×10-8 M. Cytotoxicity data showed that voacamine did not exhibit cytotoxicity at concentrations lower than 0.32 µM. However, it exerted significant immunosuppressive effect on B cells at a lower concentration, but had no influence on proliferation of T cells. Autodock results indicate that voacamine has a good interaction with the enzyme active site. Conclusion: Voacamine and its analogues exert influence on the immune system

IN SILICO STUDY OF BIOACTIVE COMPOUNDS FROM SUNGKAI (PERONEMA CANESCENS) AS IMMUNOMODULATOR

Objective: This study aims to predict a bioactive compound from Peronema canescens (PC) with mechanisms inhibitor interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) potential as an immunomodulatory using in silico approach. Methods: Autodock 4 was used to accomplish computer-assisted drug design with molecular docking simulation to discover binding energy, inhibition constant, and interactions with an amino acid in bioactive compounds from PC against IL-6 and TNF-α receptors. Lipinski predicts the drug-likeness of a bioactive compound for the oral route of administration. ADMET profiling of bioactive compounds to predict pharmacokinetic properties with pkCSM ADMET. Results: The results showed that the best binding energy, inhibition constant, and interactions with an amino acid of peronemin C1 against IL-6 and TNF-α receptors were (-7.19 kcal/mol; 5.39 nM; Arg 179, Arg 182, Gln 175), and (-8.86 kcal/mol; 320.42 nM; Tyr 119, Tyr 59, and Gly 121), respectively. All bioactive compounds from PC met Lipinski's rule of five requirements for oral administration. ADMET prediction results all bioactive compounds from PC are non-mutagenic, except peronemin D1 is mutagenic. Conclusion: The peronemin C1 bioactive compounds from PC have good immunomodulatory potential, effectively inhibiting human IL-6 and TNF-α receptors using in silico approach

In-silico design of novel myocilin inhibitors for glaucoma therapy

Purpose: To explore newer computational approaches in the design of novel myocilin inhibitors for the treatment of glaucoma.Methods: An in-silico virtual screening technique based on simulation of molecular docking was utilised to design a novel myocilin inhibitors for the treatment of  glaucoma. The designed novel molecules were theoretically evaluated to predict their pharmacokinetic properties and toxic effects. Lead molecules were screened out in virtual screening technique on the basis of low binding energies obtained in AutoDock based molecular docking simulation.Results: Out of ten top lead compounds screened, ZINC01729523 and ZINC04692015 were promising, having shown potent inhibition of myocilin, good pharmacokinetic properties and absence of any toxic effects.Conclusion: In-silico virtual screening of molecular libraries containing a large number of ligands is very useful for short-listing of potential lead molecules for further structure-based discovery of antiglaucoma-drugs.Keywords: Glaucoma, Myocilin, Docking, Virtual-screening, Autodock, Ligand, Drug desig

ANTIDIABETIC ACTIVITY OF NOVEL CHROMENE COMPOUND ISOLATED FROM PEPEROMIA PELLUCIDA L. KUNTH AND IN SILICO STUDY AGAINST DPP-IV, ALPHA-GLUCOSIDASE, ALPHA-AMYLASE, AND ALDOSE REDUCTASE FOR BLOOD GLUCOSE HOMEOSTASIS

Objective: During the outbreak of COVID-19, diabetes mellitus (DM) and cardiovascular disease (CVD) become risk factors for severe adverse clinical outcomes in COVID-19 patients. DM is a complex metabolic disease originating from a process of requiring adequate insulin or due to insulin resistance. This in silico study reveals the molecular interaction of Peperochromene A ((S)-2-methyl-2-(4-methylpent-3-enyl)-6-(propan-2-ylidene)-3,4,6,7-tetrahydropyrano[4,3-g]chromen-9(2H)-one), a novel chromene compound isolated from Peperomia pellucida with four proteins involved in the homeostasis of blood glucose, namely dipeptidylpeptidase-IV (DPP-IV), α-glucosidase, α-amylase, and aldose reductase. Methods: Molecular docking simulation of the ligands was performed by employing AutoDock 4.2 embedded in LigandScout at a certain position determined automatically by the program. The default parameters of the automatic settings were used to set the genetic algorithm parameters. Results: Peperochromene A could interact with all four targets; however, it binds to alpha-glucosidase and α-amylase with Ki (inhibition constant) value better than that of acarbose, the enzymes’ known inhibitor. This chromene compound also reveals an inhibition constant to aldose reductase similar with that of the enzyme inhibitor. Conclusion: The chromene isolated from Peperomia pellucida is the potential to be developed as an inhibitor of the proteins involved in the homeostasis of blood glucose; thus, it can be further explored for its antidiabetic activity

Elucidation of the mechanisms underlying the anticholecystitis effect of the Tibetan medicine “Dida” using Network pharmacology

Purpose: To study the mechanism involved in the anti-cholecystitis effect the Tibetan medicine “Dida”, using network pharmacology-integrated molecular docking simulationsMethods: In this investigation, the bioactive compounds of Dida were collected, network pharmacology methods to predict their targets, and networks were constructed through GO and KEGG pathway analyses. The potential binding between the bioactive compounds and the targets were demonstrated using molecular docking simulations.Results: A total of 12 bioactive compounds and 50 key targets of Dida were identified. Two networks, namely, protein-protein interaction (PPI) network of cholecystitis targets, and compound-target-pathway network, were established. Network analysis showed that 10 targets (GAPDH, AKT1, CASP3, EGFR, TNF, MAPK3, MAPK1, HSP90AA1, STAT3, and BCL2L1) may be the therapeutic targets of Dida in cholecystitis. Analysis of the KEGG pathway indicated that the anti-cholecystitis effect of Dida may its regulation of a few crucial pathways, such as apoptosis, as well as toll-like  receptor, T cell receptor, NOD-like receptor, and MAPK signaling pathways. Furthermore, molecular docking simulation revealed that CASP3, CAPDH, HSP90AA1, MAPK3, MAPK1, and STAT3 had well-characterized interactions with the corresponding compounds.Conclusion: The mechanism underlying the anti-cholecystitis effect of Dida was successfully predicted and verified using a combination of network pharmacology and molecular docking simulation. This provides a firm basis for the experimental verification of the use of Dida in the treatment of cholecystitis, and enhances its rational application in clinical medication. Keywords: Tibetan medicine, Dida, Cholecystitis, Mechanism of effect, Network pharmacology, Molecular docking simulatio

The antennal transcriptome analysis and characterizations of odorant-binding proteins in Megachile saussurei (Hymenoptera, Megachilidae)

Background Odorant-binding proteins (OBPs) are essential in insect’s daily behaviors mediated by olfactory percep‑ tion. Megachile saussurei Radoszkowski (Hymenoptera, Megachilidae) is a principal insect pollinating alfalfa (Medicago sativa) in Northwestern China. The olfactory function have been less conducted, which provides a lot of possibilities for our research. Results Our results showed that 20 OBPs were identifed in total. Multiple sequence alignment analysis indicated MsauOBPs were highly conserved with a 6-cysteine motif pattern and all belonged to the classic subfamily, coding 113-196 amino acids and sharing 41.32%-99.12% amino acid identity with known OBPs of other bees. Phylogenetic analysis indicated there were certain homologies existed among MsauOBPs and most sequences were clustered with that of Osmia cornuta (Hymenoptera, Megachilidae). Expression analysis showed the identifed OBPs were mostly enriched in antennae instead of other four body parts, especially the MsauOBP2, MsauOBP3, MsauOBP4, MsauOBP8, MsauOBP11 and MsauOBP17, in which the MsauOBP2, MsauOBP4 and MsauOBP8 presented obvious tissue-biased expression pattern. Molecular docking results indicated MsauOBP4 might be the most signifcant protein in recogniz‑ ing alfalfa fower volatile 3-Octanone, while MsauOBP13 might be the most crucial protein identifying (Z)-3-hexenyl acetate. It was also found the lysine was a momentous hydrophilic amino acid in docking simulations. Conclusion In this study, we identifed and analyzed 20 OBPs of M. saussurei. The certain homology existed among these OBPs, while some degree of divergence could also be noticed, indicating the complex functions that diferent MsauOBPs performed. Besides, the M. saussurei and Osmia cornuta were very likely to share similar physi‑ ological functions as most of their OBPs were clustered together. MsauOBP4 might be the key protein in recognizing 3-Octanone, while MsauOBP13 might be the key protein in binding (Z)-3-hexenyl acetate. These two proteins might contribute to the alfalfa-locating during the pollination process. The relevant results may help determine the highly specifc and efective attractants for M. saussurei in alfalfa pollination and reveal the molecular mechanism of odorevoked pollinating behavior between these two species